Valproic Acid Decreases Urothelial Cancer Cell Proliferation and Induces Thrombospondin-1 Expression.

BMC Urology (Impact Factor: 1.41). 08/2012; 12(1):21. DOI: 10.1186/1471-2490-12-21
Source: PubMed


Prevention of bladder cancer recurrence is a central challenge in the management of this highly prevalent disease. The histone deacetylase inhibitor valproic acid (sodium valproate) has anti-angiogenic properties and has been shown to decrease bladder cancer growth in model systems. We have previously shown reduced expression of thrombospondin-1 in a mouse model and in human bladder cancer relative to normal urothelium. We speculated that inhibition of angiogenesis by valproate might be mediated by this anti-angiogenic protein.

Bladder cancer cell lines UMUC3 and T24 were treated with valproate or another histone deacetylase inhibitor, vorinostat, in culture for a period of three days. Proliferation was assessed by alamar blue reduction. Gene expression was evaluated by reverse transcription of RNA and quantitative PCR.

Proliferation assays showed treatment with valproate or vorinostat decreased proliferation in both cell lines. Histone deacetylase inhibition also increased relative expression of thrombospondin-1 up to 8 fold at 5 mM valproate.

Histone deacetylase inhibitors warrant further study for the prevention or treatment of bladder cancer.

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    • "Valproic acid (VPA), a potent anticonvulsant that also acts as an HDACI, produces a paucity of side-effects in humans, even when serum levels exceed the normal therapeutic range while receiving anti-epileptic therapy (6). The drug alters the expression of a critical subset of target genes (7), and this selective modulation probably explains the therapeutic efficiency and mild adverse effects. Furthermore, VPA also has useful pharmacokinetic properties, with a significantly longer biological half-life than the other HDACIs (8). "
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